RalA functions as an indispensable signal mediator for the nutrient-sensing system.
Cells sense nutrients present in the extracellular environment and modulate the activities of intracellular signaling systems in response to nutrient availability. This study demonstrates that RalA and its activator RalGDS participate in nutrient sensing and are indispensable for activation of mammalian target of rapamycin complex 1 (mTORC1) induced by extracellular nutrients. Knockdown of RalA or RalGDS abolished amino acid- and glucose-induced mTORC1 activation, as judged by phosphorylation of S6 kinase and eukaryotic translation initiation factor 4E-binding protein 1. The amount of GTP-bound RalA increased in response to increased amino acid availability. In addition, RalA knockdown suppressed Rheb-induced S6 kinase phosphorylation, and the constitutively active form of RalA induced mTORC1 activation in the absence of Rheb. These results collectively suggest that RalGDS and RalA act downstream of Rheb and that RalA activation is a crucial step in nutrient-induced mTORC1 activation.
Maehama
Tomohiko
T
Department of Biochemistry and Cell Biology, National Institute of Infectious Diseases, Tokyo 162-8640, Japan. tmaehama@nih.go.jp
Tanaka
Masahiko
M
Nishina
Hiroshi
H
Murakami
Makoto
M
Kanaho
Yasunori
Y
Hanada
Kentaro
K
D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism; D018797:Cell Cycle Proteins; D049109:Cell Proliferation; D006367:HeLa Cells; D006801:Humans; D015151:Immunoblotting; D000076222:Mechanistic Target of Rapamycin Complex 1; D008954:Models, Biological; D020559:Monomeric GTP-Binding Proteins / Q000378:metabolism*; D046912:Multiprotein Complexes; D009479:Neuropeptides / Q000378:metabolism*; D010750:Phosphoproteins / Q000378:metabolism; D011506:Proteins; D034622:RNA Interference; D000076205:Ras Homolog Enriched in Brain Protein; D020133:Reverse Transcriptase Polymerase Chain Reaction; D019893:Ribosomal Protein S6 Kinases / Q000378:metabolism; D015398:Signal Transduction; D058570:TOR Serine-Threonine Kinases; D013997:Time Factors; D014157:Transcription Factors / Q000378:metabolism; D020725:ral GTP-Binding Proteins / Q000737:chemistry* / Q000378:metabolism; D020726:ral Guanine Nucleotide Exchange Factor / Q000378:metabolism*
D048868:Adaptor Proteins, Signal Transducing; D018797:Cell Cycle Proteins; C087000:EIF4EBP1 protein, human; D046912:Multiprotein Complexes; D009479:Neuropeptides; D010750:Phosphoproteins; D011506:Proteins; C490211:RHEB protein, human; C483163:Ralb protein, human; D000076205:Ras Homolog Enriched in Brain Protein; D014157:Transcription Factors; D020726:ral Guanine Nucleotide Exchange Factor; D000076222:Mechanistic Target of Rapamycin Complex 1; D019893:Ribosomal Protein S6 Kinases; D058570:TOR Serine-Threonine Kinases; C492198:RALA protein, human; D020559:Monomeric GTP-Binding Proteins; D020725:ral GTP-Binding Proteins